Reprogramming pancreatic cells into insulin makers to treat diabetes

University of Geneva scientists showed that human alpha and gamma pancreatic cells can be reprogrammed to produce insulin. (Pedro Herrera/UNIGE)

Diabetes occurs when the insulin-producing beta cells of the pancreas are destroyed or become dysfunctional. Scientists are keen to find methods for regenerating these cells to treat diabetes. Now, researchers at the University of Geneva (UNIGE) have converted other pancreatic cells into cells that can secrete insulin, and they have shown promising results in treating mouse models of diabetes.

Five types of cells that produce different hormones cluster together in the pancreas to form what’s known as pancreatic islets. Among them, human alpha and gamma endocrine cells can be modified to fill in for beta cells and produce insulin, the Swiss team reported in a study published in Nature.

Pedro Herrera and colleagues at UNIGE had previously showed that the mouse pancreas can spontaneously change its identity to produce insulin. To test whether a similar mechanism exists in human cells, the scientists built pseudo-islets that were made up of only one noninsulin-producing cell type.

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Simply aggregating the single-functioning cells stimulated the expression of genes linked to insulin production, “as if the ‘non-beta’ cells naturally detected the absence of their ‘sisters,’” Kenichiro Furuyama, the study’s first author, said in a statement. However, these cells didn’t start producing insulin until the researchers added proteins that control the transcription of beta cell-specific genes.

Increased expression of two key transcription factors, PDX1 and MafA, enabled alpha and gamma cells to produce insulin, the team found.

When these pseudo-islets were transplanted into mice that lacked insulin-producing beta cells, the rodents recovered from Type 1 diabetes, as their glucose tolerance and blood levels became normal, according to the team. The cells continued to secrete human insulin six months after transplantation, and the results were the same with cells derived from both diabetic and nondiabetic donors.

Because Type 1 diabetes is marked by an autoimmune attack against beta cells, the researchers wanted to make sure their modified cells didn’t become new targets of the immune system. To their relief, the cells, when cocultured with T cells from patients with Type 1 diabetes, triggered a weaker immune response, making the researchers optimistic that the cells might be less likely to be destroyed than native beta cells.

RELATED: Regenerating insulin-producing cells with zinc could tackle the underlying cause of diabetes

Replacing missing or dysfunctional beta cells remains a popular target among researchers trying to find a cure for diabetes. Scientists at Stanford University recently used zinc to guide a regenerative medicine to beta cells, for example. A team at the University of Miami located pancreatic stem cells that they showed can develop into beta cells. And AstraZeneca and Ionis are working together on antisense oligonucleotides to silence genes linked to reduced insulin production.

UNIGE’s findings provide early evidence for human pancreatic cells’ ability to change function when certain cellular conditions are met. But Herrera cautioned that more work needs to be done before the discovery can be turned into a treatment.

“We must indeed find a way—pharmacological or by gene therapy—to stimulate this change of identity in the cells concerned within the patient's own pancreas, but without causing adverse effects on other cell types,” he said.

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